Missense mutations result in abrogation of p53 tumor suppressive function leading to a GOF that promotes cancers.[5] Collective evidence from our laboratory and others indicates that acetylation destabilizes mutant p53, and contributes to structural and chemical remodeling, solubility promotion, and reactivation of mutant p53.[15, 17, 60, 61] We propose that the GOF of missense mutant p53 comes from the hard‐to‐drive acetylation because of Smad1 occupying p300, thereby, emphasizing the decisive role of acetylation in determining tumor suppressor properties of p53 in GBM. The gene discussed is SMAD1; the disease is glioblastoma.